Ruey-Long Hong

Decision on Final Phase II dose; Guidelines combination dose level adjustments in the phase Ib phase; Schema for dose adjustments if more than 2 patients have DLT; Definitions of DLT

Changes of cell types based on (a) MCP-Counter and (b) Danaher module with post- vs pre-treatment samples. All tests were performed by non-parametric Wilcoxon test.

Supplementary Table 1a. Differentially expressed genes between Post-treatment vs Pre-treatment; Supplementary Table 1b. Differentially expressed genes between Responders vs Nonresponders; Supplementary Table 1c. Differentially expressed genes between PFS longer than 6 months vs PFS shorter than 6 months.

Volcano plots of differentially expressed genes of different clinical scenarios (a) partial responders vs non-partial responders (b) progression-free survival longer vs shorter than 6 months (c) post- and pre-treatment samples.

Cell type predictive of treatment efficacy. Cell type differences of (a) partial response vs non-partial responders (b) progression-free survival longer vs shorter than 6 months by MCP-Counter. All p-values were derived from non-parametric Wilcoxon test.

Purpose:Satisfactory treatment options for advanced leiomyosarcoma and liposarcoma are limited. The LEADER study (NCT03526679) investigated the safety and efficacy of lenvatinib plus eribulin.Patients andMethods:LEADER is a multicenter phase Ib/II study for advanced leiomyosarcoma or liposarcoma. The phase Ib part enrolled 6 patients to determine the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) with the starting dose of lenvatinib 18 mg/day and eribulin 1.1 mg/m2 D1, D8 every 21 days. The primary endpoint of the phase II part was objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors 1.1, with phase Ib patients preplanned to be included in the efficacy analysis. Translational analyses were based on the transcriptomic data obtained from the NanoString nCounter platform.Results:Thirty patients were enrolled (leiomyosarcoma 21, liposarcoma 9); the median age was 59. One patient had to temporarily stop lenvatinib due to grade 2 arthritis in the first cycle, meeting DLT criteria. Four of 6 patients had to decrease the dose of lenvatinib to 14 mg between cycles two and three. RP2D was determined at lenvatinib 14 mg/day and eribulin 1.1 mg/m2. The confirmed ORR was 20%, and the ORR was not significantly different between phase Ib/II cohorts (P = 0.23). The median progression-free survival was 8.56 months (95% confidence interval, 4.40–not reached). Translational studies suggested increased dendritic cells in the tumor microenvironment (TME) after treatment.Conclusions:Lenvatinib plus eribulin has a manageable safety profile and exhibits promising efficacy for treating advanced leiomyosarcoma and liposarcoma.